The prognostic influence of tumour-infiltrating lymphocytes in cancer: a systematic review with meta-analysis.
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ABSTRACT: Background
Tumour-infiltrating lymphocytes (TILs) are often found in tumours, presumably reflecting an immune response against the tumour. We carried out a systematic review and meta-analysis, aiming to establish pooled estimates for survival outcomes based on the presence of TILs in cancer.Methods
A Pubmed and Embase literature search was designed. Studies were included, in which the prognostic significance of intratumoural CD3+, CD4+, CD8+, and FoxP3+ lymphocytes, as well as ratios between these subsets, were determined in solid tumours.Results
In pooled analysis, CD3+ TILs had a positive effect on survival with a hazard ratio (HR) of 0.58 (95% confidence interval (CI) 0.43-0.78) for death, as did CD8+ TILs with a HR of 0.71 (95% CI 0.62-0.82). FoxP3+ regulatory TILs were not linked to overall survival, with a HR of 1.19 (95% CI 0.84-1.67). The CD8/FoxP3 ratio produced a more impressive HR (risk of death: HR 0.48, 95% CI 0.34-0.68), but was used in relatively few studies. Sample size and follow-up time seemed to influence study outcomes.Conclusion
Any future studies should be carefully designed, to prevent overestimating the effect of TILs on prognosis. In this context, ratios between TIL subsets may be more informative.
SUBMITTER: Gooden MJ
PROVIDER: S-EPMC3137407 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe role of tumour infiltrating lymphocytes (TILs) as a biomarker in non-invasive breast cancer is unclear. This meta-analysis assessed the prognostic impact of TIL levels in patients with non-invasive breast cancer.MethodsSystematic literature search was performed to identify studies assessing local recurrence in patients with non-invasive breast cancer according to TIL levels (high vs. low). Subgroup analyses per local recurrence (invasive and non-invasive) were performed. Secondary objectives were the association between TIL levels and non-invasive breast cancer subtypes, age, grade and necrosis. Odds ratios (ORs) and 95% confidence intervals (CI) were extracted from each study and a pooled analysis was conducted with random-effect model.ResultsSeven studies (N = 3437) were included in the present meta-analysis. High-TILs were associated with a higher likelihood of local recurrence (invasive or non-invasive, N = 2941; OR 2.05; 95%CI, 1.03-4.08; p = 0.042), although with a lower likelihood of invasive local recurrence (N = 1722; OR 0.69; 95%CI, 0.49-0.99; p = 0.042). High-TIL levels were associated with triple-negative (OR 3.84; 95%CI, 2.23-6.61; p < 0.001) and HER2-positive (OR 6.27; 95%CI, 4.93-7.97; p < 0.001) subtypes, high grade (OR 5.15; 95%CI, 3.69-7.19; p < 0.001) and necrosis (OR 3.09; 95%CI, 2.33-4.10; p < 0.001).ConclusionsHigh-TIL levels were associated with more aggressive tumours, a higher likelihood of local recurrence (invasive or non-invasive) but a lower likelihood of invasive local recurrence in patients with non-invasive breast cancer.
| S-EPMC8319525 | biostudies-literature
Project description:ObjectivesSome studies have identified tumour-infiltrating lymphocytes (TILs) in H&E-stained sections of gastric cancer, but the prognostic and clinicopathological significance of this remains unclear. The objective of this study is to evaluate the associations between H&E-based TIL density and prognosis and clinicopathological characteristics of patients with gastric cancer.DesignSystematic review and meta-analysis.Data sourcesCochrane Library, PubMed and Embase databases were searched through 25 February 2020.Eligibility criteriaStudies evaluating the correlations between TILs assessed by H&E-stained sections and prognosis and clinicopathological characteristics of gastric cancer were included.Data extraction and synthesisRelevant data were extracted and risks of bias were assessed independently by two reviewers. HR and relative risk (RR) with 95% CI were pooled by random-effect models to estimate the associations between TIL density and overall survival (OS) and clinicopathological characteristics, respectively.ResultsWe enrolled nine studies including 2835 cases for the present meta-analysis. High TILs were associated with superior OS (HR=0.68, 95% CI 0.52 to 0.87, p=0.003) compared with low TILs. High TILs were significantly associated with lower depth of invasion (T3-T4 vs T1-T2) (RR=0.58, 95% CI 0.50 to 0.66, p<0.001), less lymph node involvement (presence vs absence) (RR=0.68, 95% CI 0.56 to 0.81, p<0.001) and earlier TNM (tumour, node, metastasis) stage (III-IV vs I-II) (RR=0.68, 95% CI 0.55 to 0.83, p<0.001). TIL density was not associated with age, gender, Lauren classification or histological grade. The methodology for evaluating TIL and its cut-off value varied across different studies, which might affect the results of our meta-analysis.ConclusionsOur meta-analysis suggests that H&E-based TIL density is a reliable biomarker to predict the clinical outcomes of patients with gastric cancer. Multicentre, prospective studies are needed to further confirm our findings.Prospero registration numberCRD42020169877.
| S-EPMC7853025 | biostudies-literature
Project description:BackgroundThe potential prognostic value of tumor-infiltrating lymphocytes (TILs) in gastric cancer remains controversial. This meta-analysis examines the association between TILs and survival outcomes in gastric cancer.MethodsTwenty-two eligible studies were identified using the PubMed and Google Scholar databases. The combined sample size of the 22 studies was 2941, and the median sample size of the individual studies was 122 patients (52-220). The main clinical outcomes examined were overall cancer survival (OCS) and overall cancer relapse-free survival (OCRFS).ResultsTumor tissue CD3(+) TILs, indicative of pan-T-cell expression, had a positive effect on survival with a hazard ratio (HR) of 0.64 (95% confidence interval [CI] 0.52-0.78) for OCS, as did the non-FOXP3(+) T-cell subgroup with an HR of 0.66 (95% CI 0.57-0.75), particularly in CD8(+) lymphocytes (HR?=?0.63, 95% CI 0.48-0.83). On the contrary, high FOXP3(+) T-cell expression was correlated with reduced OCS, with an HR of 1.75 (95% CI 1.26-2.42). Analysis of the seven studies evaluating OCRFS revealed improved OCRFS with infiltration of non-FOXP3(+) TILs with an HR of 0.59 (95% CI 0.42-0.81) but not FOXP3(+) T lymphocytes with an HR of 1.82 (95% CI 1.30-2.53).ConclusionThe results from this meta-analysis suggest that high expression of TILs, mainly by CD8 lymphocytes, may be a potential prognostic biomarker in patients with gastric cancer.
| S-EPMC6133557 | biostudies-literature
Project description:Tumor-infiltrating lymphocytes (TILs) are an important histopathologic feature of colorectal cancer that confer prognostic information. Previous clinical and epidemiologic studies have found that the presence and quantification of tumor-infiltrating lymphocytes are significantly associated with disease-specific and overall survival in colorectal cancer. We performed a systematic review and meta-analysis, establishing pooled estimates for survival outcomes based on the presence of TILs in colon cancer. PubMed (Medline), Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov were searched from inception to April 2017. Studies were included, in which the prognostic significance of intratumoral tumor infiltrating lymphocytes, as well as subsets of CD3, CD8, FOXP3, CD45R0 lymphocytes, were determined within the solid tumor center, the invasive margin, and tumor stroma. Random-effects models were calculated to estimated summary effects using hazard ratios. Forty-three relevant studies describing 21,015 patients were included in our meta-analysis. The results demonstrate that high levels of generalized TILS as compared to low levels had an improved overall survival (OS) with a HR of 0.65 (p = <0.01). In addition, histologically localized CD3+ T-cells at the tumor center were significantly associated with better disease-free survival (HR = 0.46, 95% CI 0.36-0.61, p = 0.05), and CD3 + cells at the invasive margin were associated with improved disease-free survival (HR = 0.57, 95% CI 0.38-0.86, p = 0.05). CD8+ T-cells at the tumor center had statistically significant prognostic value on cancer-specific survival and overall survival with HRs of 0.65 (p = 0.02) and 0.71 (p < 0.01), respectively. Lastly, FOXP3+ T-cells at the tumor center were associated with improved prognosis for cancer-specific survival (HR = 0.65, p < 0.01) and overall survival (HR = 0.70, p < 0.01). These findings suggest that TILs and specific TIL subsets serve as prognostic biomarkers for colorectal cancer.
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Project description:BackgroundThe prognostic values of tumor-infiltrating lymphocytes (TILs) and TILs subsets in breast cancer (BC) are uncertain.MethodsA systematic literature search (MEDLINE, Web of Science, EMBASE, and the Cochrane Library to August 2014) was conducted for studies which met the eligibility criteria. The primary clinical outcome was defined as disease-free survival (DFS), overall survival (OS), and BC-specific survival (BCSS). Random or fixed-effects model was adopted to estimate the summary hazard ratio (HR).ResultsTwenty-five published studies comprising 22,964 patients were reviewed. Pooled analysis indicated that TILs were not prognostic markers for DFS and OS in overall population, but related to improved DFS (HR, 0.82; 95% CI, 0.76-0.88) and OS (HR, 0.79; 95% CI, 0.71-0.87) in triple negative breast cancer (TNBC) patients. For TILs subsets, CD8+ lymphocytes were associated with improved DFS (HR, 0.69; 95% CI, 0.56-0.84) and BCSS (HR, 0.78; 95% CI, 0.71-0.86) in overall population, while FOXP3+ lymphocytes were associated with reduced DFS (HR, 1.47; 95% CI, 1.01-2.05) and OS (HR, 1.50; 95% CI, 1.15-1.97). In estrogen receptor (ER) negative patients, CD8+ lymphocytes was also related to better BCSS. In addition, the high density of CD20+, CD3+ or low level of PD-1+ or γδ T lymphocytes indicated increased OS in limited studies.ConclusionTILs and TILs subsets are promising prognostic biomarkers in breast cancer, especially in TNBC.
| S-EPMC4830515 | biostudies-literature
Project description:BackgroundBreast cancer is the most common invasive cancer to affect women in the world. Studies showed tumor-infiltrating lymphocytes can exhibit both beneficial and harmful effects on the biology and clinical outcome of breast cancer, the conclusion still remains incomplete. Here, we conducted a meta-analysis to evaluate the relationship between tumor-infiltrating lymphocytes and breast cancer.MethodsA comprehensive search strategy was used to search relevant literatures in PubMed and the ISI Web of Science. The correlation among TILs and breast cancer clinicopathological features and prognosis was analyzed by using Review Manager 5.3 and Stata 12.0.ResultSeventeen eligible studies consisting of 12,968 participants were included. We found that higher value of tumor-infiltrating lymphocytes had no relationship with breast cancer clinicopathological variables. Interestingly, it was correlated with response to neoadjuvant chemotherapy in majority (pooled RR 2.43, 95% CI 1.99-2.97). Moreover, higher value of total tumor-infiltrating lymphocytes (both intraepithelial and stromal) was associated with better prognosis (pooled HR 0.88, 95% CI 0.83-0.94), whereas some subtypes predicted a worse prognosis.ConclusionThis meta-analysis indicated that high value of total TILs is not associated with breast cancer clinicopathological features, but can predict a favorable outcome for neoadjuvant chemotherapy in majority except for hormone receptor (-) subtype. And higher total TILs (both intraepithelial TILs and stromal TILs) may be the potential better prognostic indicators, while some subtypes like PD-1(+) TILs and Foxp3(+) TILs show a worse prognosis.
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Project description:Tumor-infiltrating lymphocytes (TILs) are associated with prognosis in various tumors. However, it remains controversial whether the presence of TILs is related to an improved prognosis in melanoma. This meta-analysis confirmed the favorable prognostic role of the CD3+, CD4+, CD8+, FOXP3+, and CD20+ TILs in the overall survival of melanoma patients and found an association between the TILs present and improved overall survival. Additionally, subgroup analysis demonstrated that brisk TILs were obviously associated with OS, RFS and DSS/MSS. Thus, TILs may be a predictive biomarker in melanoma. This analysis will provide more insight into the study of TILs and predictive biomarker.
| S-EPMC6527267 | biostudies-literature
Project description:BackgroundTumor-infiltrating lymphocytes (TILs) are involved in the antitumor immune response. The association between prognosis in patients with TILs and high-grade serous ovarian cancer (HGSOC) remains obscure, with some studies reporting conflicting results.MethodsWe conducted an extensive literature search of electronic databases and retrieved prognostic data of each selected subtype of TILs, including CD3+, CD4+, CD8+, CD103+, and PD-1+ TILs. The fixed-effects model was applied to derive the pooled hazard ratio (HR) and 95% confidence interval (CI) of these markers.ResultsThe systematic review process yielded 19 eligible studies comprising 6004 patients with HGSOC. We compared TIL-positive and TIL-negative patients, and the pooled HRs from the multivariate analysis revealed that intraepithelial CD8+ TILs were positively correlated with progression-free survival (PFS, HR 0.46, 95% CI 0.25-0.67) and overall survival (OS, HR 0.90, 95% CI 0.86-0.9); stromal CD8+ TILs were positively correlated with OS (HR 0.61, 95% CI 0.36-0.87). Furthermore, the pooled HRs from univariate analysis demonstrated that intraepithelial CD3+, CD4+, CD8+, and CD103+ TILs were positively associated with OS (HR 0.58, 95% CI 0.44-0.72; HR 0.37, 95% CI 0.16-0.59; HR 0.51, 95% CI 0.42-0.60, and HR 0.59, 95% CI 0.44-0.74, respectively); stromal CD4+ and CD8+ TILs were significantly associated with OS (HR 0.63, 95% CI 0.32-0.94 and HR 0.78, 95% CI 0.58-0.97, respectively). However, the pooled HR from the multivariate analysis revealed that PD-1+ TILs were not associated with the OS of patients with HGSOC (HR 0.97, 95% CI 0.90-1.04).ConclusionThis meta-analysis provided evidence of the association of CD3+, CD4+, CD8+, and CD103+ TILs with the survival benefits (OS and PFS) of patients with HGSOC.
| S-EPMC7607723 | biostudies-literature
Project description:BACKGROUND:The objective of this systematic review and meta-analysis was to determine the prognostic value of total tumor-infiltrating lymphocytes (TILs) and subtypes of TILs (CD4+, CD8+, and FOXP3+) in triple-negative breast cancer (TNBC). METHODS:A systematic search of the MEDLINE, EMBASE, and Web of Science databases was conducted to identified eligible articles published before August 2019. Study screening, data extraction, and risk of bias assessment were performed by two independent reviewers. Risk of bias on the study level was assessed using the ROBINS I tool and Quality in Prognosis Studies (QUIPS) tool. We performed a meta-analysis to obtain a pooled estimate of the prognostic role of TILs using Review Manager 5.3. RESULTS:In total, 37 studies were included in the final analysis. Compared to TNBC patients with low TIL levels, TNBC patients with high TIL levels showed a higher rate of pathological complete response (pCR) to treatment (odds ratio [OR] 2.14, 95% confidence interval [CI] 1.43-3.19). With each 10% increase in percentage of TILs, patients with TNBC had an increased pCR (OR 1.09, 95% CI 1.02-1.16). Compared to TNBC patients with low TIL levels, patients with high TIL levels had better overall survival (OS; hazard ratio [HR] 0.58, 95% CI 0.48-0.71) and disease-free survival (DFS; HR 0.66, 95% CI 0.57-0.76). Additionally, with a continuous increase in TIL levels, patients with TNBC had improved OS (HR 0.90, 95% CI 0.87-0.93) and DFS (HR 0.92, 95% CI 0.90-0.95). A high CD4+ TIL level was associated with better OS (HR 0.49, 95% CI 0.32-0.76) and DFS (HR 0.54, 95% CI 0.36-0.80). A high CD8+ TIL level was associated better DFS only (HR 0.55, 95% CI 0.38-0.81), as no statistical association was found with OS (HR 0.70, 95% CI 0.46-1.06). A high FOXP3+ TIL level also was associated with only DFS (HR 0.50, 95% CI 0.33-0.75) and not OS (HR 1.28, 95% CI 0.24-6.88). CONCLUSIONS:TNBC with a high level of TILs showed better short-term and long-term prognoses. High levels of specific phenotypes of TILs (CD4+, CD8+, and FOXP3+) were predictive of a positive long-term prognosis for TNBC.
| S-EPMC7057662 | biostudies-literature
Project description:Previous clinical studies have found that the levels of tumor-infiltrating lymphocytes (TILs) significantly correlated with prognosis in hepatocellular carcinoma (HCC). However, these conclusions and data remain controversial. We performed a systematic review and meta-analysis to assess the prognostic value and clinical utilization of TILs in patients with HCC. A total of 23 relevant studies of 3173 patients were included into our meta-analysis. The results demonstrated that high levels of CD8 + and CD3 + TILs had a better prognostic value on overall survival (OS), with HRs of 0.71 (P = 0.04) and 0.63 (P = 0.03), respectively, compared to low levels, as did high levels of CD8 + , CD3 + and CD4 + TILs on disease/recurrence-free survival (DFS/RFS), with HRs of 0.66 (P = 0.01), 0.60 (P = 0.01) and 0.79 (P = 0.04), respectively. In contrast, high levels of FoxP3 + TILs had a worse prognostic value on OS and DFS/RFS, with HRs of 2.06 (P < 0.00001) and 1.77 (P < 0.00001), respectively. The FoxP3+/CD4+ and FoxP3+/CD8+ ratios negatively correlated with OS and DFS/RFS. These findings suggest that TILs may serve as a prognostic biomarker in HCC. However, further research should be performed to clarify the clinical value of TILs in HCC.
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